The Inhibitory Effect of Ginsan on TGF-β Mediated Fibrotic Process

Transforming growth factor-beta (TGF-beta) plays a central role in the development of fibrosis by stimulating extracellular matrix accumulation, and signals either directly or indirectly through types I, II, and III (T beta RI, II, and III) TGF-beta receptor complexes. Ginsan, a polysaccharide extracted from Panax ginseng, has multiple immunomodulatory effects. Here, we examine whether ginsan regulates the fibrogenic process by interfering with TGF-beta signaling pathways. TGF-beta treatment of murine or human normal lung fibroblasts enhanced the levels of several fibrotic markers, including smooth muscle alpha actin (alpha-SMA), collagen-1, and fibronectin. Interestingly, ginsan treatment either before or after TGF-beta administration led to significant reductions in all of alpha-SMA, collagen-1, and fibronectin expression levels. Ginsan not only inhibited phosphorylation of Smad2 and Smad3, but also attenuated pERK and pAKT signaling induced by TGF-beta. Moreover, ginsan restored T beta RIII protein expression, which was significantly downregulated by TGF-beta, but reduced T beta RI and T beta RII protein levels. In a murine model of bleomycin (BLM)-induced pulmonary fibrosis, ginsan significantly suppressed accumulation of collagen, alpha-SMA, and TGF-beta. These data collectively suggest that ginsan acts as an effective anti-fibrotic agent in the treatment of pulmonary fibrosis by blocking multiple TGF-beta signaling pathways. J. Cell. Physiol. 226: 1241-1247, 2011. (C) 2010 Wiley-Liss, Inc.